WO2009127140A1 - Peptide 7p et son dérivé, ainsi que leur utilisation - Google Patents

Peptide 7p et son dérivé, ainsi que leur utilisation Download PDF

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Publication number
WO2009127140A1
WO2009127140A1 PCT/CN2009/071204 CN2009071204W WO2009127140A1 WO 2009127140 A1 WO2009127140 A1 WO 2009127140A1 CN 2009071204 W CN2009071204 W CN 2009071204W WO 2009127140 A1 WO2009127140 A1 WO 2009127140A1
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WIPO (PCT)
Prior art keywords
oligopeptide
group
pharmaceutically acceptable
ester
acceptable salt
Prior art date
Application number
PCT/CN2009/071204
Other languages
English (en)
Chinese (zh)
Inventor
程云
虞瑞鹤
赵万洲
赵军
郭仁锋
Original Assignee
Cheng Yun
Yu Ruihe
Zhao Wanzhou
Zhao Jun
Guo Renfeng
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CNA2008101044251A external-priority patent/CN101559217A/zh
Priority claimed from CNA2008101046045A external-priority patent/CN101565452A/zh
Application filed by Cheng Yun, Yu Ruihe, Zhao Wanzhou, Zhao Jun, Guo Renfeng filed Critical Cheng Yun
Priority to CN200980101141XA priority Critical patent/CN101883781B/zh
Publication of WO2009127140A1 publication Critical patent/WO2009127140A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1021—Tetrapeptides with the first amino acid being acidic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids

Definitions

  • the present invention is in the field of peptide pharmacology, and in particular, the present invention relates to 7P and its derived oligopeptide or a pharmaceutically acceptable salt or ester thereof, especially a novel 7P-derived oligopeptide. Further, the present invention relates to a pharmaceutical composition, a kit, a preparation method and a pharmaceutical application containing such an oligopeptide, particularly for the prevention and/or treatment of new uses such as nephritis.
  • the peptide having the sequence GQTYTSG (abbreviated as 7P herein) is an immunogenic peptide originally designed according to the hepatitis C virus, and the inventors disclosed the use as the type C in the Chinese specialties ljCN1194986C and CN1216075C, respectively. 7P of hepatitis virus immunogenic peptide and a partial derivative thereof. In addition, in PCT application WO20 07/137456A, the inventors have also discovered that 7P and its partial derivatives can also be used for the prevention and/or treatment of liver damage, in particular for preventing or treating immune liver damage and/or liver. Liver damage caused by toxic chemicals.
  • the routes of administration in the above examples of the examples are all injections, since peptide drugs are subject to low intestinal tract The absorption rate, the degradation caused by peptidase in the digestive system, and the short half-life after absorption in the living body, the development of oral peptide preparations is still in its infancy, no major progress, and currently developed and commercialized peptides Most of the drugs are in the form of injections, and it is inevitable that the patients will receive the pain and cumbersome procedures brought about by injection. Especially for preventive drugs, such an injection route will make it difficult for patients to adhere to prophylactic administration for a long time.
  • One of the objects of the present invention is to provide novel 7P-derived peptides, including 7P truncated peptides and 7P variant peptides, which are not GQTYTSG, GQTYTSGAs and GQTYTSGG. Further, the present invention also provides a pharmaceutical composition, a kit, and the like comprising the novel 7P-derived peptide, and a preparation method thereof, and a prophylactic and therapeutic application thereof for liver damage and nephritis, particularly for liver damage Prevention and treatment.
  • the second object of the present invention is to provide a method for preventing and treating new diseases such as chronic immune liver damage, liver-induced liver damage and nephritis by using 7P and 7P-derived peptides, in particular, 7P for preventing and treating nephritis.
  • the present invention also provides an application for preparing a corresponding drug, and a corresponding pharmaceutical composition, a kit, and the like.
  • the third object of the present invention is to provide a method for digestive administration of 7 ⁇ and 7 ⁇ derived peptides and corresponding preparations
  • the invention provides a 7 ⁇ and 7 ⁇ derived peptide or a pharmaceutically acceptable salt or ester thereof, i.e., the invention provides an oligopeptide of formula I or a pharmaceutically acceptable thereof Salt or ester,
  • Xaa3 is Thr or Ser
  • Xaa4 is Tyr, Phe, Trp or Val
  • Xaa5 is missing, Ser or Thr, [18] Xaa6 is missing, Gly or Ala, and
  • Xaa7 is a deletion, Ala or Gly.
  • the first aspect of the invention preferably provides novel 7P and 7P derived peptides or pharmaceutically acceptable salts or esters thereof, i.e., preferably provides an oligopeptide of formula I or a pharmaceutically acceptable salt or ester thereof, wherein the oligopeptide is not Gly-Gln-Thr-Tyr-Thr-Ser-Gly-Xaa7, wherein X aa 7 is a deletion, Ala or G ly (ie, the oligopeptide is not GQTYTSG, GQTYTSGA, and GQTYTSGG).
  • amino acid or amino acid residues can be defined in Table 1, and these abbreviations may refer to L-type amino acids, and may also refer to D-type amino acids.
  • amino acid or amino acid residue refers to an L-form amino acid or amino acid residue.
  • deletion as used herein means that the deleted amino acid residue is not present in the peptide sequence.
  • Xaa7 when Xaa7 is deleted, Xaa6 in the sequence of Formula I is the C-terminal amino acid of the sequence of Formula I; when Xaa2 is deleted, if Xaal and Xaa3 are present, IJXaal is directly linked to Xaa3.
  • Suitable modifications are prepared as multimers, towards terminal amino groups, carboxyl groups or
  • the side chain group is modified to form a pharmaceutically acceptable ester, a conjugate comprising a sequence of Formula I, a fusion protein comprising a sequence of Formula I, or a combination of such modifications, etc., which may also be encompassed by the present invention.
  • cyclization of a linear peptide such as condensation of the amino group at the N-terminus of the peptide with the carboxyl group at the C-terminus, can generally extend the half-life of the peptide in a physiological environment.
  • ester refers to an ester which is suitable for contact with the tissues of a human or animal without excessive toxicity, irritation or allergies and the like. In general, esterification can reduce the hydrolysis of peptides by proteases in the body. Modification of the terminal amino, carboxyl or side chain groups of the peptides of the invention can form pharmaceutically acceptable esters. Modifications to the amino acid side chain groups include, but are not limited to, the esterification of threonine, a serine side chain hydroxyl group with a carboxylic acid.
  • Modifications of the N-terminal amino group include, but are not limited to, de-amino, N-lower fluorenyl, N-di-lower fluorenyl, and N-acyl modification.
  • Modifications of the C-terminal carboxyl group include, but are not limited to, amides, lower mercaptoamides, dinonylamides, and lower mercaptoester modifications.
  • the terminal group is protected with a protecting group known to those skilled in the art of protein chemistry, such as acetyl, trifluoroacetyl, Fmoc (9-fluorenyl-methoxycarbonyl), Boc
  • the amino group at the N-terminus of the polypeptide and the carboxyl group at the C-terminus and the amino acid side chain group are modified, that is, the chemical group at the N-terminus is still the a-amino group (-NH 2 ) on the first amino acid.
  • the chemical group at the C-terminus is the carboxyl group (-COOH) of the C-terminal amino acid.
  • the present invention also preferably acylates the carboxyl group at the C-terminus, that is, the chemical group at the C-terminus is -CO NH 2 .
  • the conjugate comprising the sequence of formula I comprises a pharmaceutically acceptable water-soluble polymer moiety using methods known in the art. Typically, the conjugate exhibits a circulating half-life of a peptide that extends the sequence of Formula I.
  • Suitable water soluble polymers include polyethylene glycol
  • PEG Polymers of monomethoxy-PEG, monomethoxy-PEG aldehyde, methoxy PEG-succinimidyl propionic acid, polyvinyl alcohol, dextran, cellulose or other saccharides .
  • Suitable PEGs can have a molecular weight of from about 600 to about 60,000, including, for example, 5,000 Daltons, 12,000 Daltons, 20,000 Daltons,
  • Conjugates of peptides comprising sequences of formula I may also include mixtures of such water soluble polymers.
  • PEGylation can be carried out by PEGylation reactions known in the art (see, for example, Delgado et al., Critical Reviews in Therapeutic Drug Carrier Systems 9: 249 (1992), Duncan and Spreafico, Clin. Pharmacokinet. 27: 290 (1994), and Francis et al, Int J Hematol 68: 1 (1998)). E.g,
  • the PEGylation can be carried out by an acylation reaction or by a thiolation reaction using a reactive polyethylene glycol molecule.
  • the conjugate is formed by a condensation-activated PEG in which the hydroxyl or amino group at the end of the PEG is replaced by an activated linker molecule (see, for example, Karasiewicz et al.
  • the conjugate comprising the sequence of formula I may also be a conjugate of a peptide of the sequence of formula I which is crosslinked with other proteins.
  • the other protein is preferably the Fc portion of a human albumin, bovine albumin or IgG molecule.
  • the peptide of the invention is crosslinked with bovine serum albumin to form a peptide conjugate.
  • the peptide of the present invention having the sequence of the formula I may also be a fusion peptide or fusion protein comprising a sequence of the formula I and a peptide or a protein of the formula I, which comprises the sequence of the formula I.
  • the protein is a human albumin, bovine albumin or Fc of an IgG molecule
  • Albumin can be genetically engineered to the peptide of the present invention containing the sequence of formula I to extend the half-life.
  • human albumin is the most common natural blood protein in the human circulatory system, which can maintain circulation in the body for more than 20 days.
  • therapeutic proteins that are genetically engineered to human albumin have a longer half-life.
  • the resulting fusion protein can increase the circulating half-life (see US 5,750,375, US 5,847,725, US Patent No. 6,291,646; Barouch et al, Journal of Immunology, 61: 1875-1882 (1998); Barouch et al, Proc. Natl. Acad. Sci. USA, 97(8): 4192-4197 (April 11, 2000); and Kim et al, Transplant Proc, 30 (8): 4031-4036 (1998))°
  • salt refers to a salt that is suitable for contact with the tissues of a human or animal without excessive toxicity, irritation or allergic reaction, and the like.
  • Pharmaceutically acceptable salts are well known in the art. Such salts may be prepared during the final isolation and purification of the polypeptides of the invention, or may be prepared separately by reacting the peptide with a suitable organic or inorganic acid or base.
  • Representative acid addition salts include, but are not limited to, acetate, dihexanoate, alginate, citrate, aspartate, benzoate, besylate, hydrogen sulfate, butyrate , camphorate, camphor sulfonate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate Acid salt, lactate, maleate, methanesulfonic acid Salt, nicotinate, 2-naphthalenesulfonate, oxalate, 3-phenylpropionate, propionate, succinate, tartrate, phosphate, glutamate, bicarbonate, p-toluene Sulfonate and undecanoate.
  • Preferred acids which can be used to form pharmaceutically acceptable salts are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, oxalic acid, maleic acid, succinic acid and citric acid.
  • the cations in the pharmaceutically acceptable base addition salts include, but are not limited to, alkali metal or alkaline earth metal ions such as lithium, sodium, potassium, calcium, magnesium, and aluminum, and non-toxic quaternary ammonium cations such as ammonium, tetramethylammonium, Tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, diethylamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.
  • Preferred base addition salts include phosphates, tris and acetates. These salts are generally capable of increasing the solubility of the polypeptide, and the salt formed does not substantially alter the activity of the polypeptide.
  • the polypeptide of the present invention may be used singly or in the form of a pharmaceutically acceptable salt.
  • the oligopeptide has an action of preventing or treating liver damage or nephritis. This can be verified by an animal model of liver injury or nephritis provided in a specific embodiment of the invention.
  • prevention and “treatment” as used herein have the meaning as commonly understood by those skilled in the art that “prevention” refers to the administration of a pharmaceutical composition or active compound prior to onset or before the onset of symptoms to prevent, delay and / or to reduce the onset of symptoms or symptoms of the corresponding disease; “treatment” means, after or after the onset of the disease, or after or after the onset of symptoms, the administration of the pharmaceutical composition or active compound to eliminate the corresponding conditions, reduce the corresponding The severity of the symptoms, or delay the development of the corresponding condition.
  • the oligopeptide according to the first aspect of the present invention comprises a TYT sequence, that is, in Formula I, Xaa3 is Thr, and Xaa4 is Tyr, and Other variable amino acid residues in Formula I can be substituted or deleted.
  • the oligopeptide of the first aspect of the invention is truncated on the basis of a 7P peptide, such as an oligopeptide obtained by removing one or two amino acid residues at the C-terminus of the 7P peptide, and/or a 7P peptide.
  • the oligopeptide according to the first aspect of the present invention is an oligopeptide obtained by centripetal truncation of a 7P peptide, that is, an oligopeptide obtained by removing one or two amino acid residues at the C-terminus and the N-terminal end of the 7P peptide.
  • Peptide an oligopeptide obtained by removing one or two amino acid residues at the C-terminus and the N-terminal end of the 7P peptide.
  • the amino acid sequence ⁇ 1 J of the oligopeptide is selected from the group consisting of GQTYTS, QTYTSGs GQTYT, QTYTS, QTYT, TYTS, and TYT.
  • the oligopeptide of the formula I described in the first aspect of the invention may be an oligopeptide obtained by substituting or deleting one or two amino acid residues in the amino acid sequence of GQTYTSG, and the oligopeptide still has Prevent or treat liver damage or nephritis. More preferably, the oligopeptide is in the amino acid sequence of GQTYTSG An oligopeptide obtained by replacing one amino acid residue, according to the experimental results of the variant peptide of the embodiment of the present invention, such a variant peptide is still mostly capable of preventing or treating liver damage.
  • the oligopeptide of the formula I described in the first aspect of the invention may be an oligopeptide obtained by substituting or deleting one or two amino acid residues in the amino acid sequence of GQTYTSG, and the oligopeptide still has Prevent or treat liver damage or nephritis. More preferably, the oligopeptide is in the amino acid sequence of GQTYTSG An oligo
  • the oligopeptide is an oligopeptide selected from the group consisting of AQTYTSG, GNTYTSGs GQSYTSG, GQTYTTG, GQTYTS As GQTFTSGs GQTWTSGs and GQTVTSG.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the oligopeptide of the first aspect of the invention or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier means a non-toxic solid, semi-solid or liquid filler, diluent, adjuvant, encapsulating material or other formulation excipient.
  • the carrier to be used may be adapted to the corresponding administration form, and may be formulated into an injection, (injectable) lyophilized powder, a spray, an oral solution, an oral suspension, a tablet, a capsule, using a carrier known to those skilled in the art.
  • Formulations such as enteric-coated tablets, pills, powders, granules, sustained release or delayed release.
  • the oligopeptide according to the first aspect of the present invention is administered by injection and by the digestive tract, and therefore, the pharmaceutical composition of the present invention is preferably an injection or a preparation for administration via the digestive tract, that is, Carriers suitable for administration by injection and administration by the digestive tract are particularly preferred.
  • digestive administration refers herein to a mode of administration of a pharmaceutical preparation through a patient's digestive tract, including oral, intragastric, and enema administration, preferably oral.
  • the carrier used may be adapted to the corresponding mode of administration, such as when administered by the digestive tract, and may be formulated into oral solutions, oral suspensions, tablets, capsules, using carriers known to those skilled in the art. Enteric-coated tablets, pills, powders, granules, sustained release or delayed release release.
  • liver injury refers to damage or lesions in liver tissue or cells. According to the cause of liver damage, liver damage can be divided into liver damage caused by viral liver damage, immune liver damage and hepatotoxic chemicals.
  • the pharmaceutical composition of the present invention is preferably used for the prevention and/or treatment of liver damage caused by immunological liver damage and/or hepatotoxic chemicals, particularly immune liver damage and alcohol-induced liver damage. According to the speed of liver injury, liver damage can be divided into acute liver injury and chronic liver injury.
  • Liver damage can be assessed by pathological phenomena (such as pathological scores of tissue samples from animal models), or by changes in serum levels of alanine aminotransferase or aspartate aminotransferase, or by malondialdehyde in liver tissue homogenate or Changes in levels such as glutathione are reflected.
  • the pharmaceutical composition of the present invention is useful for prevention and/or treatment of liver damage which is acute Immunological liver injury and chronic immune liver injury, such as D-galactosamine-induced acute liver injury, galactosamine and Freund's complete adjuvant-induced chronic immune liver injury and serum-induced chronic immune liver injury.
  • a pharmaceutical composition comprising a novel 7P-derived peptide has been shown to be useful for the prevention and/or treatment of acute immune liver injury.
  • a pharmaceutical composition comprising 7P is shown to be useful for the prevention and/or treatment of chronic immune liver damage and alcohol-induced liver damage, and the pharmaceutical composition may be administered via the digestive tract. The preparation greatly reduces the pain of the patient's administration.
  • the present invention provides the use of the oligopeptide of the first aspect of the present invention or a pharmaceutically acceptable salt or ester thereof for the preparation of a medicament for preventing and/or treating liver damage.
  • the oligopeptide is preferably a novel 7P-derived peptide, ie the oligopeptide is an oligopeptide of formula I, and is not Gly-Gln-Thr-Tyr-Thr-Ser-Gly-Xaa7, wherein X aa 7 is deleted , Ala or Gly.
  • the liver damage is an immune liver injury such as chronic immune liver damage and acute immune liver damage; it is also preferable that the liver damage is liver damage caused by hepatotoxic chemicals, particularly alcohol-induced liver damage.
  • the drug is a pharmaceutical preparation for injection or administration via the digestive tract. According to a specific embodiment of the present invention, it is also preferred that 7P or a pharmaceutically acceptable salt or ester thereof is used for the preparation of a medicament for preventing and/or treating chronic immunological liver injury or alcohol-induced liver damage, more preferably wherein The drug is a pharmaceutical preparation for administration via the digestive tract.
  • the process for preparing a medicament comprises the step of mixing the oligopeptide of the first aspect of the invention or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier, for formulation into a liver for preventing and/or treating Injured pharmaceutical preparation.
  • the manner in which the drug is prepared can be prepared into a suitable formulation by a method familiar to those skilled in the art to enable administration of the corresponding formulation.
  • the present invention provides a method of preventing and/or treating liver damage comprising administering to a subject an effective amount of the oligopeptide of the first aspect of the invention or a pharmaceutically acceptable thereof Accepted salt or ester.
  • subject refers to a mammal, especially a human. According to the equivalent dose conversion relationship between experimental animals and humans known to those skilled in the art (see generally the guidance of FDA, SFDA and other drug regulatory agencies, see also "Huang Jihan et al. Pharmacological tests in animals and animals and Equivalent dose conversion between humans. Chinese Journal of Clinical Pharmacology and Therapeutics, 2004 Sep;9(9)
  • the effective dose of a human can be derived from the dose of the experimental animal.
  • the "effective amount” herein refers to an effective dose of a human, unless otherwise specified.
  • the effective amount of human is 0.1. ⁇ 100 ⁇ ⁇ / Kg body weight, preferably 0.5 to 5 ( ⁇ g/Kg body weight, more preferably 1 to 3 ( ⁇ g/Kg body weight, more preferably 1.5 to 25 g)
  • the effective amount of human is 1 to 100 ( ⁇ g/Kg body weight) Preferably, it is 10 to 300 ⁇ ⁇ / ⁇ g body weight, more preferably 30-12 ( ⁇ g/Kg body weight, most preferably an effective amount is converted according to a specific embodiment of the present invention.
  • the oligopeptide is New 7P-derived peptides; moreover, it is preferred that liver damage is immune liver damage, including chronic immune liver damage and acute immune liver damage; it is also preferred that liver damage is liver damage caused by hepatotoxic chemicals, especially alcohol-induced liver Further, it is preferred that the administration mode is injection or transgastric administration. According to a specific embodiment of the present invention, a method of preventing and/or treating chronic immunological liver injury, which comprises administering an effective amount to a subject, is also preferred.
  • the tester is administered an effective amount of 7P or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutically acceptable salt or ester thereof, more preferably wherein the mode of administration is by the digestive tract.
  • the mode of administration may be a single administration.
  • the drug may also be administered multiple times, such as administering an effective amount of the above oligopeptide multiple times at intervals of one week.
  • the pharmaceutical composition of the second aspect of the invention may also be used for the prevention and/or treatment of nephritis.
  • nephritis refers to inflammation of kidney tissue or cells.
  • nephritis is serum albumin-induced nephritis and active Heymann's nephritis.
  • Nephritis can be assessed by pathological phenomena (such as pathological scores of tissue samples from animal models) or by physiological and biochemical levels such as urea nitrogen levels, creatinine levels, and average nucleated cell counts in the glomeruli.
  • a pharmaceutical composition comprising 7P is shown to be useful for the prevention and/or treatment of nephritis.
  • the present invention provides the use of the oligopeptide of the first aspect of the present invention or a pharmaceutically acceptable salt or ester thereof for the preparation of a medicament for preventing and/or treating nephritis.
  • the oligopeptide is 7P; moreover, nephritis is serum albumin-induced nephritis and active Heymann's nephritis.
  • the drug is a pharmaceutical preparation for injection or administration via the digestive tract, and particularly preferably an injectable pharmaceutical preparation.
  • the process for preparing a medicament comprises the step of mixing the oligopeptide of the first aspect of the invention, or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier, for formulation and for use in the prevention and/or treatment of nephritis Pharmaceutical preparations.
  • the manner in which the drug is prepared can be prepared into a suitable formulation by a method familiar to those skilled in the art to enable administration of the corresponding formulation.
  • the present invention provides a method of preventing and/or treating nephritis comprising administering to a subject an effective amount of the oligopeptide of the first aspect of the invention or a pharmaceutically acceptable thereof Salt or ester.
  • the "subject” means a mammal, preferably a human; preferably, the administration is by injection or by the digestive tract, and particularly preferably by injection; in addition, the "effective amount” generally means an effective dose for human.
  • the effective amount of human is 0.1 to 10 ( ⁇ g/kg body weight, preferably 0.5 to 5 ( ⁇ g/kg body weight, more preferably 1 to 3 ( ⁇ g/kg body weight, more preferably 1.5 to 25 g/kg body weight, more preferably 10 to 20 ⁇ ⁇ /13 ⁇ 4 body weight, most preferably an effective amount is converted according to a specific embodiment of the present invention; for oral administration, the effective amount of human is 1 to 1000 ⁇ ⁇ /] 3 ⁇ 4
  • the body weight is preferably 10 to 30 ( ⁇ g/Kg body weight, more preferably 30-12 ( ⁇ g/Kg body weight).
  • the oligopeptide is preferably 7P; moreover, nephritis is preferably serum Albumin-induced nephritis and active Heymann's nephritis.
  • the administration may be a single administration or multiple administrations, such as administering an effective amount of the above oligopeptide multiple times at intervals of one week.
  • the present invention provides a kit comprising
  • a container comprising the oligopeptide of the first aspect of the invention or a pharmaceutically acceptable salt or ester thereof;
  • the kit is a packaged pharmaceutical form well known to the public, and includes a container containing a medicament, such as a bottle, a tube, etc., and includes instructions, which can be contained in a separate form in the kit, also It can be printed on the outer wall of the cartridge or container.
  • the specification provides the oligopeptide or the pharmaceutically acceptable salt or ester thereof according to the first aspect of the present invention, which is administered according to the fourth aspect or the sixth aspect of the present invention. And/or treatment of liver damage or nephritis.
  • the content may include one or more of indications, dosages, and modes of administration, for example, the content may be prevention or treatment of chronic immunological liver injury and/or prevention by administering an effective amount of 7P via the digestive tract. Or treat nephritis.
  • the present invention provides a method of synthesizing the oligopeptide of the first aspect of the invention.
  • the oligopeptide of the present invention can be synthesized by a chemical method such as a solid phase method or a liquid phase method which is commonly used in peptide synthesis, and can be efficiently synthesized by functional group protection and deprotection as needed.
  • a protecting group such as an amino group used in peptide synthesis, a condensing agent for a condensation reaction, and the like are available in the prior art, and are commercially available synthetic devices and reagents, such as various commercially available ones in the solid phase method.
  • Peptide synthesis device The synthesis of peptides of known structure by chemical methods will be apparent to those skilled in the art.
  • the polypeptide of the invention is preferably synthesized by a solid phase method.
  • the oligopeptide precursor of the first aspect of the present invention can also be produced by a biorecombination technique, and the oligopeptide according to the first aspect of the present invention can be chemically or enzymatically cleaved.
  • a DNA sequence encoding a peptide containing the oligopeptide is prepared, introduced into a recombinant vector, transformed into a host, and the desired oligopeptide precursor is isolated and purified by culturing the expression host, and then the oligopeptide is chemically or enzymatically cleaved.
  • FIG. 1 Effect of different 7P truncated peptides on serum alanine aminotransferase activity in rat galactosamine-induced liver injury, where ** indicates that the group shown can significantly reduce transaminase levels relative to the model group, * indicates the indicated group The level of transaminase can be significantly reduced relative to the model group.
  • Figure 2 Effect of different 7P truncated peptides on serum aspartate aminotransferase activity in rat galactosamine-induced liver injury, where ** indicates that the group shown can significantly reduce transaminase levels relative to the model group, * indicates that the indicated group is relatively The model group was able to significantly reduce transaminase levels.
  • FIG. 1 Effect of different 7P truncated peptides on the pathological score of galactosamine liver injury in rats, where ** indicates that the group shown can significantly reduce the pathology score relative to the model group, * indicates that the indicated group is relatively The model group was able to significantly reduce the pathology score.
  • FIG. Administration of 7P via digestive tract to BCG and lipopolysaccharide-induced acute immune liver injury in mice The effect of enzyme levels, where ** indicates that the group shown can significantly reduce transaminase levels relative to the model group.
  • * indicates that the indicated group can significantly reduce transaminase levels relative to the model group.
  • * indicates that the indicated group can significantly reduce transaminase levels relative to the model group.
  • FIG. Effect of 7P administered by the digestive tract on pathological scores of acute immune liver injury induced by BCG and lipopolysaccharide in mice, where ** indicates that the group shown can significantly reduce liver damage compared to the model group.
  • Figure 7 Effect of 7P administered by the digestive tract on the level of alanine aminotransferase in chronic immunological liver injury induced by galactosamine and Freund's complete adjuvant, where ** indicates that the group shown can be relative to the model group. The level of transaminase was significantly reduced, and * indicates that the indicated group was able to significantly reduce transaminase levels relative to the model group.
  • Figure 8 Effect of 7P administered by the digestive tract on the level of aspartate aminotransferase in chronic immunological liver injury induced by galactosamine and Freund's complete adjuvant, wherein ** indicates that the group shown can be very Significantly reduced transaminase levels, * indicates that the indicated groups were able to significantly reduce transaminase levels relative to the model group.
  • FIG. 9 Effect of 7P administered by the digestive tract on pathological scores of chronic immunological liver injury induced by galactosamine and Freund's complete adjuvant, wherein ** indicates that the group shown can be very Significantly reduce the pathological score of liver injury, * indicates that the indicated group can significantly reduce the pathological score of liver injury relative to the model group.
  • Figure 10 Effect of peptide 7P administered by the digestive tract on serum alanine aminotransferase levels in rats with hepatic injury induced by xenogeneic serum, wherein ** indicates that the group shown can significantly reduce transaminase levels relative to the model group, * indicates The indicated group was able to significantly reduce transaminase levels relative to the model group.
  • FIG. 11 Effect of peptide 7P administered by the digestive tract on serum aspartate aminotransferase levels in rats with hepatic injury induced by xenogeneic serum, where ** indicates that the group shown can significantly reduce transaminase levels relative to the model group, * indicates The group was able to significantly reduce transaminase levels relative to the model group.
  • FIG. 12 Effect of peptide 7P administered by the digestive tract on hepatic pathology scores in rats with hepatic injury induced by xenogeneic serum, wherein ** indicates that the group shown can significantly reduce the pathological score of liver injury relative to the model group, * It is indicated that the indicated group can significantly reduce the pathological score of liver injury relative to the model group.
  • Figure 13.7P Effect on bovine serum albumin-induced urea nitrogen levels in rat nephritis, where ** indicates that the group shown is significantly different from the model group, and * indicates that the group shown is significantly different from the model group.
  • Figure 14.7P Effect on bovine serum albumin-induced creatinine levels in rat nephritis, where ** indicates that the group shown is significantly different from the model group, and * indicates that the group shown is significantly different from the model group.
  • Figure 16.7 shows the effect of bovine serum albumin on the average number of nucleated cells in the glomeruli of rat nephritis, where ** indicates that the group shown is significantly different from the model group, and * indicates that the group shown is relative to The model group is significantly different.
  • Figure 17.7 shows the effect of the same rat kidney cortex homogenate plus Freund's complete adjuvant on the urea nitrogen level in rats with active Heymann's nephritis AHN), where ** indicates that the group shown is very different from the model group, * Indicates that the group shown is significantly different from the model group.
  • Figure 18.7 shows the effect of the same rat kidney cortex homogenate plus Freund's complete adjuvant on the creatinine level of active Heymann's nephritis (AHN) rats, where ** indicates that the group shown is very different from the model group, * Indicates that the group shown is significantly different from the model group.
  • Figure 19.7P Effect on pathological scores of rats with active Heymann's nephritis AHN) established by homologous rat renal cortex homogenate plus Freund's complete adjuvant, where ** indicates that the indicated group is very significant relative to the model group, * Indicates that the group shown is significantly different from the model group.
  • Figure 21.7 Effect of P variant peptide on D-galactosamine-induced serum biochemical ALT in rats with acute liver injury. Where ** indicates that the group shown is very different from the model group, and * indicates that the group shown is significantly different from the model group.
  • Figure 23.7 Effect of P variant peptide on D-galactosamine-induced pathological scoring of acute liver injury in rats, where ** indicates that the group shown is significantly different from the model group, * indicates that the group shown is relative to The model group is significantly different.
  • Figure 24. Effect of peptide 7P administered by the digestive tract on MDA levels in rats with alcohol-induced liver injury, where ** indicates that the group shown can significantly reduce MDA levels relative to the model group, * indicates that the group shown is relative The model group can significantly reduce MDA levels.
  • FIG. 25 Effect of peptide 7P administered by the digestive tract on GSH levels in rats with alcohol-induced liver injury, where ** indicates that the group shown can significantly increase GSH levels relative to the model group, * indicates that the group shown is relatively The model group can significantly increase the GSH level.
  • FIG. 26 Effect of peptide 7P administered by the digestive tract on the pathological score of rats with alcohol-induced liver injury, where ** indicates that the group shown is significantly different from the model group, * indicates that the group shown is relative to the model Group differences are significant.
  • a peptide as shown in the following sequence was synthesized by a solid phase peptide synthesis method using an automatic peptide synthesizer Model 413A (available from PerkinElmer Co., Ltd.): GQTYTSG (abbreviated as 7P); 7P truncated peptide:
  • GQTYTS (referred to as PI), QTYTSG (referred to as P2), GQTYT (referred to as P3), QTY TS (referred to as P4), QTYT (referred to as P5), TYTS (referred to as P6), TYT (referred to as P7)
  • the 7P synthesized in Example 1 was crosslinked with bovine serum albumin (BSA) by a glutaraldehyde method to form a conjugate.
  • BSA bovine serum albumin
  • the specific conjugation process is as follows: 1 mg of the 7P synthesized in Example 1 is dissolved in 0.5 ml of PBS (pH 7.4, 0.02 mol/L); 4.5 mg is taken.
  • Drug dosage and grouping Experimental animals were randomly divided into 11 groups, namely, blank control group, model group, and positive drug (Ganlixin injection) group (the dose was 13.5 mg/kg. day in terms of diammonium glycyrrhizinate). ), 7P group (87 g/kg « day), 7 truncated peptide groups (ie, Pl, P2, P3, P4, P5, P6, P7 groups, respectively, doses of 87 g / k days), each group 10 SPF grade SD rats (body weight 180g ⁇ 220g, male and female).
  • the model group, the positive drug group, the 7P group and the P1 ⁇ P7 group were intraperitoneally injected with D-aminogalactosamine 600 mg/kg rat body weight, and the injection volume was 1 ml/100 g rat.
  • the blank group was injected with the same amount of normal saline.
  • the rats were weighed first, and the blood was separated. The serum was separated and the alanine aminotransferase and aspartate aminotransferase activities were determined using alanine aminotransferase and aspartate aminotransferase assay kits.
  • the rats were sacrificed by cervical dislocation and histological examination of liver tissue was performed. According to the degree of light to heavy lesions marked as 0, 0.5,
  • the liver injury model replicated in this experiment is mainly characterized by punctate or small focal necrosis of multifocal hepatocytes and inflammatory cell infiltration at the necrosis. Eosinophils appeared in the liver cells, and a small amount of inflammatory cells infiltrated around the central vein and in the portal area. Fibroplasia was not observed in the portal area. Mild lipid changes are seen in most rat liver cells. It is distributed in a small stove. For D-galactosamine-induced acute liver injury in rats, different peptide sequences can reduce the degree of liver damage after application. The results are in order of high to low: 7P group, Pl, P2, P3,
  • the dose was 175 g/kg based on BCG polysaccharide
  • the blank group was injected with the same amount of normal saline.
  • the model group, the positive drug group and the 7P group were injected with 10 ⁇ - lipopolysaccharide (LPS) in the tail vein, and the blank group was injected with the same amount of normal saline.
  • LPS ⁇ - lipopolysaccharide
  • alanine aminotransferase and aspartate aminotransferase activities were determined by alanine aminotransferase and aspartate aminotransferase assay kits, respectively. After the mice were sacrificed by cervical dislocation, an autopsy was performed to perform histopathological examination of the liver tissue.
  • the histopathological study of 7P on BCG and lipopolysaccharide-induced immunological liver injury in mice showed that the mouse model of acute immune liver injury replicated in this study was mainly characterized by subcapsular hepatocyte degeneration and hepatocyte pyknosis. .
  • a small number of hepatocytes have mild necrosis, and a small amount of inflammatory cells infiltrate around the central vein. No fibrous tissue hyperplasia was seen in the portal area.
  • the 7P high- and medium-dose groups could significantly reduce the degree of hepatocyte injury after intragastric administration (P ⁇ 0.01).
  • the low-dose 7P group also significantly reduced the degree of hepatocyte injury after intragastric administration ( ⁇ 0 ⁇ 05) (See Figure 6).
  • Model preparation BALB/, rats were injected intraperitoneally with galactosamine 300mg/kg, and the same abdominal cavity was injected subcutaneously with Freund's complete adjuvant 0.05ml/20g once a week for four weeks; then, abdominal cavity Injection of galactosamine 400mg/kg, subcutaneous injection of Freund's complete adjuvant 0.05ml/20g, once a week, Eight weeks in a row; then, galactosamine 500 mg/kg was intraperitoneally injected into the abdomen with a subcutaneous injection of Freund's complete adjuvant 0.1 ml/20 g of mouse body weight once a week for six weeks.
  • mice 100 samples of chronic immunological liver injury in mice were successfully prepared by serum samples, and randomly divided into 5 groups, P model group and positive drug (Ganlixin injection) group (the dose was measured by diammonium glycyrrhizinate). 19.5mg/kg.day), 7P high dose group (1250 ⁇ ⁇ / kg. day), 7P medium dose group (625 ⁇ ⁇ /
  • mice Kg. days
  • 7P low-dose group 312.5 g/kg. day
  • the same batch of healthy mice into a blank control group, a total of 6 groups, 20 in each group.
  • mice were administered once a day, and administered continuously for 1 month (15 times in total).
  • the drugs were all prepared to the required concentration with physiological saline, and the 7P group (administered by gavage) was administered.
  • 0.2 ml/20 g, positive drug (Ganlixin injection) group was intravenously injected with glycyrrhizin, and the blank control group and model group were given an equal volume of normal saline.
  • the mice were sacrificed, weighed, and the blood was separated. Serum was separated using OLYMPUS.
  • Model preparation Wistar rats were intraperitoneally injected with 0.3ml/200g of pig serum (containing 27mg protein), one to two times a week, for three and a half months (20 times in total), and the liver function was detected by serum biochemistry. Sixty rats with chronic immunological liver injury model were prepared. The experimental animals were randomly divided into 5 groups, 12 rats in each group, namely the model group and the Ganlixin injection group (the dosage was 13.5 mg/kg.day for diammonium glycyrrhizinate), and the 7P high dose group (870 ⁇ ). ⁇ / 13 ⁇ 4 ⁇ day), 7 ⁇ medium dose group (435 g/kg. day), 7P low dose group (217.5 ⁇ ⁇ / kg. day); another 12 healthy rats were used as blank control group.
  • Group 7P was prepared with physiological saline to the required concentration, the dosage volume was 0.2 ml/200 g, administered by intragastric administration; the Ganlixin injection group was administered by tail vein injection; the blank control group and the model group were given. Equal volume of saline. Rats were administered once a day for 1 month (15 times in total), during which rats were intraperitoneally injected with porcine serum once a week (0.3 ml/200 g). After the end of the administration, the body weight was weighed, the blood was separated, and the serum was separated. The alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) were measured by an automatic biochemical analyzer.
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • TBIL total bilirubin
  • Alkaline phosphatase (AKP), total protein (TP), albumin (ALB), globulin (G), white ball ratio (A/G), and blood glucose (GLU).
  • TP total protein
  • ALB albumin
  • G globulin
  • GLU white ball ratio
  • X average score
  • liver injury model replicated in this experiment mainly showed fibrotic tissue proliferation in the hepatic lobules and in the portal area, and the fibrous tissues of the hyperplasia were connected to each other. However, it has not been wrapped, and the hepatic lobules are separated to form false leaflets. Hepatocyte degeneration is not obvious, and most rats only see a small amount of lipid droplet vacuoles in individual liver cells.
  • the high-dose group of 7P gavage administration reduced the degree of liver fibrosis, and there was a significant difference compared with the model group (P ⁇ 0.05) (see Figure 12).
  • Example 8 Protective effect of 7P on bovine serum albumin (BSA)-induced rat nephritis
  • SD rats were randomly divided into 6 groups, namely, the blank control group, the model group, and the positive drug (dexamethasone injection) group (0.9 mg/kg.day as dexamethasone).
  • the 7P high dose group (174 ⁇ /13 ⁇ 4* days), the 7P medium dose group (87 ⁇ /13 ⁇ 4* days), and the 7P low dose group (43.5 ⁇ /13 ⁇ 4* days), 10 rats in each group.
  • Each of the 7P dose groups was administered subcutaneously in a dose of 0.1 ml/100 g body weight; the dexamethasone injection group was intraperitoneally administered at a dose of 0.1 ml/100 g body weight.
  • Bovine serum albumin (BSA) was administered to the model group, the positive drug (dexamethasone injection) group, the 7P high dose group, the 7P medium dose group, and the 7P group at a dose of 150 mg Zkg body weight 12 days before the experiment.
  • Rats in the low-dose group were pre-immunized by intraperitoneal injection once, and were intraperitoneally injected once every 300 mg Zkg body weight on the first day and the 12th day of the experiment.
  • the blank control rats were replaced with an equal volume of normal saline.
  • the positive drug (dexamethasone injection) group, the 7P high-dose group, the 7P medium-dose group, and the 7P low-dose group were administered subcutaneously for dexamethasone or 7P-subjects every other day.
  • the blank control group and the model group were subcutaneously injected with an equal volume of normal saline one day at a time, and a total of 15 times were administered.
  • the rats were weighed first, the blood was separated, the serum was separated, and the creatinine (Cre-S) sarcosine oxidase assay kit and the urea nitrogen (BUN) UV-GLDH assay kit were isolated. The instructions determine creatinine and urea nitrogen.
  • an autopsy was performed. The kidney tissues were fixed with 10% formaldehyde, embedded in paraffin, sectioned, and stained with HE for histopathological examination.
  • the 7P high- and medium-dose group significantly reduced urea nitrogen (BUN) and creatinine (Cre-S) ⁇ ( ⁇ ( ⁇ or ! ⁇ ..) in experimental nephritis rats (see Figures 13, 14).
  • BUN urea nitrogen
  • Cre-S creatinine
  • the liver injury model replicated in this experiment is mainly characterized by an increase in glomerular volume, an increase in the number of nucleated cells, a lobulated glomerulus, a widening of the mesangial area, and an increase in the matrix.
  • Model animals were randomly divided into 5 groups, namely the model group and the positive drug (dexamethasone injection) group (0.9 mg/kg.day as dexamethasone).
  • 7P high dose group (174 ⁇ /13 ⁇ 4* days), 7P medium dose group (87 ⁇ /13 ⁇ 4* days), 7P low dose group (43 ⁇ 5 ⁇ ⁇
  • the 7P high-dose group, the 7P medium-dose group, and the 7P low-dose group were administered subcutaneously every other day for 15 times.
  • the blank group and the model group were subcutaneously injected with an equal volume of physiological saline one day at intervals of 15 times.
  • the rats were first weighed, the blood was separated, and the serum was separated.
  • Cre-S creatinine oxidase assay kit and urea nitrogen (BUN) UV-GLDH assay reagent The cartridge instructions determine creatinine and urea nitrogen.
  • an autopsy was performed.
  • the kidney tissues were fixed with 10% formaldehyde, embedded in paraffin, sectioned, and stained with HE for histopathological examination.
  • BUN urea nitrogen
  • Cre-S creatinine
  • renal tubular epithelial cells are severely turbid and swollen, and some renal tubular epithelium is almost eosinophilic necrosis, the lumen is obviously narrow or even occluded, and different types of tubular types can be seen in the renal tubule lumen.
  • the high-dose group of the drug showed a significant improvement in the lesion glomerulus, the glomerular volume was only slightly enlarged, the endothelial cell proliferation was not obvious, and the renal tubular epithelial cells were not.
  • Example 10 Administration of 7P in the digestive tract protects against alcoholic liver injury in mice
  • SPF-class ICR mice (body weight 18-22 g, male and female, purchased from Nantong University Experimental Animal Center) were randomly divided into nine groups of 10 animals each, including: blank control group (distilled water) Acute alcoholic liver injury model group (administered 50% ethanol solution), Tianqing Ganping positive drug group (administered diammonium glycyrrhizinate enteric-coated capsule, which was purchased from Jiangsu Zhengda Tianqing Pharmaceutical Co., Ltd., administered The dosage is 58.5 mg/kg ⁇ +50% ethanol solution with diammonium glycyrrhizinate enteric solution), and the high dose group of SP drug (administer 7P)
  • mice were administered by intragastric administration once a day for 30 consecutive days. On the 30th day, the mice were intragastrically administered with 50% absolute ethanol solution, and the mice were sacrificed after 16 hours. After weighing the mice in each group, they were sacrificed. About 0.19 ⁇ 0.25 g of fresh liver was added, and 2 ml of 0.9% normal saline was added to prepare 10% liver tissue homogenate.
  • MDA malondialdehyde
  • GSH reduced glutathione

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Abstract

La présente invention concerne un peptide ayant une séquence de formule I: Xaa1-Xaa2-Xaa3-Xaa4-Thr-Xaa5-Xaa6-Xaa7, ainsi que son sel ou ester pharmaceutiquement acceptable. L’invention concerne également la composition pharmaceutique, une trousse, un procédé de préparation et ses utilisations, en particulier pour la prévention et/ou le traitement de dommage hépatique et de la néphrite.
PCT/CN2009/071204 2008-04-18 2009-04-09 Peptide 7p et son dérivé, ainsi que leur utilisation WO2009127140A1 (fr)

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WO2013044499A1 (fr) * 2011-09-30 2013-04-04 Cheng Yun Applications d'un peptide immunogène du virus de l'hépatite c ou de ses dérivés pour la préparation d'un médicament prophylactique ou thérapeutique de la colite

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013044499A1 (fr) * 2011-09-30 2013-04-04 Cheng Yun Applications d'un peptide immunogène du virus de l'hépatite c ou de ses dérivés pour la préparation d'un médicament prophylactique ou thérapeutique de la colite

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